Career Development Plan Summary Dr. Hughes-Austin is currently an Integrated Cardiovascular Epidemiology postdoctoral fellow in the Department of Family and Preventive Medicine at the University of California, San Diego. Prior training in physical therapy and epidemiology and research experience in cardiovascular and autoimmune disease converge through both the research plan and training activities outlined in this Mentored Research Scientist Development Award. Dr. Hughes-Austin's career objective is to improve health and wellbeing in the general population through applying principles and findings observed in rheumatologic disease patients to the general population. Dr. Hughes-Austin's long-term career goal is to achieve excellence as an independently funded research scientist working in prevention of chronic diseases. Her immediate goals are to gain knowledge and experience in cardiovascular and bone immunology, bone epidemiology, and integrating these complex systems, as well as to develop the skills necessary to design, execute and analyze randomized clinical trials. UCSD is recognized as one of the nation's top academic and research institutions. It provides numerous opportunities for continued training in coursework as well as established infrastructure and programs devoted to supporting young investigators. Capitalizing on the strong institutional environment, Dr. Hughes-Austin has assembled a team of mentors and consultants with expertise in the areas of cardiovascular epidemiology, bone disease epidemiology, immunology, biostatistics, rheumatology, and clinical trials. Her mentors will not only provide tutorials within their respective areas of expertise and guidance throughout the proposed research project, but will also offer opportunities for intellectual interaction and development beyond the academic setting. Research Plan Summary Cardiovascular disease and osteoporosis affect more than one-third of older adults, and the underlying pathology of these two disease processes involves similar mechanisms. They associate, however, inversely with one another, as lower bone mineral density is associated with a higher prevalence and severity of vascular calcification and higher risk of future CVD events, independent of age and other shared risk factors. Antibodies to citrullinated protein antigens (ACPA) are self-directed antibodies to peptidyl citrulline. While citrullinated proteins occur normally, they become antigenic under inflammatory conditions, thus eliciting a self- directed immune response. ACPA have been linked to bone loss and CVD in rheumatoid arthritis patients and select populations without rheumatoid arthritis. Dr. Hughes-Austin and others have shown that ACPA are detectable in normal healthy control individuals as well. Whether ACPA are associated with CVD and bone disease in the general population, however, remains unknown. If so, their measurement may provide new insights into a novel aspect of inflammatory stress and its impact on both CVD and bone disease; diseases which jointly contribute to substantial morbidity and mortality within the non-rheumatoid arthritis general population. In this study, we propose an efficiently designed ancillary study to the NHLBI funded Multi-Ethnic Study of Atherosclerosis (MESA). Among 1968 multi-ethnic, community-dwelling men and women, our objectives are to determine the independent associations of ACPA with (1) subclinical CVD and incident development of clinical CVD events, and (2) bone mineral density within the MESA cohort. In addition, (3) as statins have known anti- inflammatory properties, we will investigate whether statin use may modify ACPA levels in 200 participants from the Pravastatin Inflammation and C - reactive protein Evaluation (PRINCE) Randomized Clinical Trial. In so doing, upon completion of this award, Dr. Hughes-Austin will be fully trained and ready to independently lead her research career. Moreover, the study will establish whether ACPA are indeed independently linked with CVD and bone disease, and will provide important information on whether or not ACPA levels are modifiable by statins. If the hypotheses prove true, this study will lead directly to Dr. Hughes-Austin's design and implementation of an intervention study to determine whether modifying ACPA may benefit CVD and bone disease in the general population.